Personalized Medicine for Non–Small-Cell Lung Cancer

It is estimated that more than 1.5 million individuals in the United States will be diagnosed with cancer this year. Of these, nearly 145,000 will be diagnosed with non–small-cell lung cancer (NSCLC). The lifetime risk of individuals developing lung cancer is about 7%, and NSCLC accounts for nearly 80% of all lung cancer cases. Until the beginning of this century, adjuvant chemotherapy was an important choice of treatment. During 2003–2005, two new targeted drugs, gefitinib (Iressa) and erlotinib (Tarceva)-both directed against the epidermal growth factor receptor (EGFR)-became available for second-line therapy. Although the progression-free and overall survival durations among NSCLC patients treated with these drugs were modest, a subset had dramatically better and sustained responses.

Stratifying Patients

Three groups have shown that the tumor DNA from patients with better responses had a certain class of mutations in the EGFR gene, whose protein product is the target of the drugs.^1-3 These initial studies were very exciting in that they suggested a possible way to stratify patient populations and determine whether tyrosine kinase inhibitor (TKI) treatment or chemotherapy is best suited for the two classes of patients. Although some groups have argued that all NSCLC tumors should be examined for their EGFR status, there was no clear consensus about the use of TKIs in first-line therapy, whether the patients should be stratified on the basis of clinical or molecular criteria, and what method of examining the status of EGFR (immunohistochemistry, fluorescence in situ hybridization [FISH], or molecular testing) is ideal for this stratification. A number of investigators have undertaken a series of clinical trials to address these and other issues related to the treatment and outcomes of these lung cancer patients.

In an article in this issue of ONCOLOGY, Oxnard and Miller⁴ summarize the results of many of these trials and provide their recommendations for treating these patients. The results from all of these clinical trials clearly show (1) erlotinib and gefitinib could be very effective in first-line therapy, (2) they are most effective for patients whose tumors have activating mutations in EGFR and are wild-type for KRAS, and (3) TKI treatment results in poorer outcomes for patients without mutations in EFGR, and this group responds better to chemotherapy.

What is remarkable about all of these trials is their internal consistency and that in the appropriate subpopulations of NSCLC patients, response rates of 60% to 80% can be achieved by identifying patients with activating mutations in EGFR in their tumors. The increases in progression-free and overall survival in unselected patients are relatively low, whereas in the appropriate selected populations, these increases are substantial. Oxnard and Miller recommend that all NSCLC tumors be examined for their EGFR status by sequence-based methods prior to determining the proper course of treatment for the approximately 145,000 new NSCLC patients/year in the United States.

Conclusions

The results summarized by Oxnard and Miller show that genetic testing is critical for clinical decision-making in this cancer. Depending on the population, the proportion of NSCLC patients who have EGFR-activating mutations may be in the range of 15% to 40%. Is it possible that the remaining set of patients have other genetic changes that might help us find a suitable treatment? It has been discovered that subsets of NSCLC patients have mutations in BRAF, mutations resulting in activation of the AKT pathway, amplification of ErbB2, amplification of MET, or translocation of EML and ALK4. Drugs that specifically target these changes are either available or in clinical trials for this or other tumor types.

Newer sequencing technologies also promise to provide a fuller understanding of the genetic and genomic changes that occur in different types of lung cancers including NSCLC. Such an understanding of the molecular changes that are present in individual tumors will help us design studies to help treat each subclass of patients most effectively. The use of EGFR testing prior to treatment decisions in NSCLC is an excellent example of personalized medicine in action. Indeed, the era of personalized cancer therapy has begun.

-Raju Kucherlapati, PhD

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

REFERENCES:1. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004.
2. Paez JG, Jänne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004.
3. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-13311, 2004.
4. Oxnard GR, Miller VA: Use of erlotinib or gefitinib as initial therapy in advanced NSCLC. Oncology (Williston Park) 24:392-399, 2010.